1. Name Of The Medicinal Product
Soliris
2. Qualitative And Quantitative Composition
2.1 General description
Eculizumab is a humanised monoclonal IgG2/4κ antibody produced in NS0 cell line by recombinant DNA technology.
2.2 Qualitative and quantitative composition
Each vial of 30 ml contains 300 mg of eculizumab (10 mg/ml).
After dilution, the final concentration of the solution to be infused is 5 mg/ml.
Excipients with known effect: Sodium (5.00 mmol per dose (1 vial))
For the full list of excipients, see section 6.1.
3. Pharmaceutical Form
Concentrate for Solution for Infusion.
Clear, colorless, pH 7.0 solution.
4. Clinical Particulars
4.1 Therapeutic Indications
Soliris (eculizumab) is indicated for the treatment of patients with
- Paroxysmal nocturnal haemoglobinuria (PNH).
Evidence of clinical benefit of Soliris in the treatment of patients with PNH is limited to patients with history of transfusions.
- Atypical haemolytic uremic syndrome (aHUS) (see section 5.1).
4.2 Posology And Method Of Administration
Soliris must be administered by a healthcare professional and under the supervision of a physician experienced in the management of patients with haematological and/or renal disorders.
Posology
In Paroxysmal Nocturnal Haemoglobinuria (PNH):
The PNH dosing regimen consists of a 4-week initial phase followed by a maintenance phase:
• Initial phase: 600 mg of Soliris administered via a 25 - 45 minute intravenous infusion every week for the first 4 weeks.
• Maintenance phase: 900 mg of Soliris administered via a 25 - 45 minute intravenous infusion for the fifth week, followed by 900 mg of Soliris administered via a 25-45 minute intravenous infusion every 14 ± 2 days (see Section 5.1).
In Atypical Haemolytic Uremic Syndrome (aHUS):
The aHUS dosing regimen for adult patients (
• Initial phase: 900 mg of Soliris via a 25 - 45 minute intravenous infusion every week for the first 4 weeks
• Maintenance phase: 1200 mg of Soliris administered via a 25 - 45 minute intravenous infusion for the fifth week, followed by 1200 mg of Soliris administered via a 25 - 45 minute intravenous infusion every 14 ± 2 days (see Section 5.1).
In paediatric aHUS patients (aged less than 12 years) and adolescent patients (aged 12 years to under 18 years), the Soliris dosing regimen consists of:
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Supplemental dosing of Soliris is required in the setting of concomitant PE/PI (plasmapheresis or plasma exchange, or fresh frozen plasma infusion):
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Method of administration
For instructions on dilution of the medicinal product before administration, see section 6.6.
Do not administer as an intravenous push or bolus injection. Soliris should only be administered via intravenous infusion as described below.
The diluted solution of Soliris should be administered by intravenous infusion over 25 – 45 minutes via gravity feed, a syringe-type pump, or an infusion pump. It is not necessary to protect the diluted solution of Soliris from light during administration to the patient.
Patients should be monitored for one hour following infusion. If an adverse event occurs during the administration of Soliris, the infusion may be slowed or stopped at the discretion of the physician. If the infusion is slowed, the total infusion time may not exceed two hours in adults and adolescents and four hours in children aged less than 12 years.
Paediatric Population: For PNH patients, no data is available in paediatric patients. For aHUS patients, the method of administration of Soliris is the same for all age groups.
Elderly: Soliris may be administered to patients aged 65 years and over. There is no evidence to suggest that any special precautions are needed when older people are treated – although experience with Soliris in this patient population is still limited.
Renal impairment: No dose adjustment is required for patients with renal impairment (see section 5.1).
Hepatic impairment: The safety and efficacy of Soliris have not been studied in patients with hepatic impairment.
Treatment monitoring:
aHUS patients should be monitored for signs and symptoms of thrombotic microangiopathy (TMA) (See section 4.4 aHUS laboratory monitoring).
Soliris treatment is recommended to continue for the patient's lifetime, unless the discontinuation of Soliris is clinically indicated (see section 4.4).
4.3 Contraindications
Hypersensitivity to eculizumab, murine proteins or to any of the excipients listed in section 6.1.
Do not initiate Soliris therapy (see section 4.4):
in PNH patients:
• with unresolved Neisseria meningitidis infection.
• who are not currently vaccinated against Neisseria meningitidis.
in aHUS patients:
• with unresolved Neisseria meningitidis infection.
• who are not currently vaccinated against Neisseria meningitidis or do not receive prophylactic treatment with appropriate antibiotics until 2 weeks after vaccination.
4.4 Special Warnings And Precautions For Use
Soliris is not expected to affect the aplastic component of anaemia in patients with PNH.
Meningococcal Infection: Due to its mechanism of action, the use of Soliris increases the patient's susceptibility to meningococcal infection (Neisseria meningitidis). These patients might be at risk of disease by uncommon serogroups (particularly Y, W135 and X), although meningococcal disease due to any serogroup may occur. To reduce the risk of infection, all patients must be vaccinated at least 2 weeks prior to receiving Soliris. Patients less than 2 years of age and those who are treated with Soliris less than 2 weeks after receiving a meningococcal vaccine must receive treatment with appropriate prophylactic antibiotics until 2 weeks after vaccination. Patients must be re-vaccinated according to current medical guidelines for vaccination use. Tetravalent vaccines against serotypes A, C, Y and W135 are strongly recommended, preferably conjugated ones.
Vaccination may not be sufficient to prevent meningococcal infection. Consideration should be given to official guidance on the appropriate use of antibacterial agents. Cases of serious or fatal meningococcal infections have been reported in Soliris-treated patients. All patients should be monitored for early signs of meningococcal infection, evaluated immediately if infection is suspected, and treated with appropriate antibiotics if necessary. Patients should be informed of these signs and symptoms and steps taken to seek medical care immediately (see Package Leaflet for a description).
Other Systemic Infections: Due to its mechanism of action, Soliris therapy should be administered with caution to patients with active systemic infections. The overall severity and frequency of infections in Soliris-treated patients was similar to placebo treated patients in clinical studies, although an increase in the number and severity of infections, particularly due to encapsulated bacteria, cannot be excluded. Patients should be provided with information from the Package Leaflet to increase their awareness of potential serious infections and the signs and symptoms of them.
Infusion Reactions: As with all therapeutic proteins, administration of Soliris may result in infusion reactions or immunogenicity that could cause allergic or hypersensitivity reactions (including anaphylaxis), though immune system disorders within 48 hours of Soliris administration did not differ from placebo treatment in PNH, aHUS and other studies conducted with Soliris. In clinical trials, no PNH or aHUS patients experienced an infusion reaction which required discontinuation of Soliris. Soliris administration should be interrupted in all patients experiencing severe infusion reactions and appropriate medical therapy administered.
Immunogenicity: Infrequent, low titre antibody responses have been detected in Soliris-treated patients across all studies. In placebo controlled studies low titre responses have been reported with a frequency (3.4%) similar to that of placebo (4.8%). No patients have been reported to develop neutralizing antibodies following therapy with Soliris, and there has been no observed correlation of antibody development to clinical response or adverse events.
Immunization: Prior to initiating Soliris therapy, it is recommended that PNH and aHUS patients should initiate immunizations according to current immunization guidelines. Additionally, all patients must be vaccinated against meningococcus at least 2 weeks prior to receiving Soliris. Patients less than 2 years of age and those who are treated with Soliris less than 2 weeks after receiving a meningococcal vaccine must receive treatment with appropriate prophylactic antibiotics until 2 weeks after vaccination. If available, tetravalent, conjugated vaccines are recommended (see meningococcal infection).
Patients less than 18 years of age must be vaccinated against haemophilus influenzae and pneumococcal infections, and strictly need to adhere to the national vaccination recommendations for each age group.
Anticoagulant therapy: Treatment with Soliris should not alter anticoagulant management.
PNH Laboratory Monitoring: PNH patients should be monitored for signs and symptoms of intravascular haemolysis, including serum lactate dehydrogenase (LDH) levels. PNH patients receiving Soliris therapy should be similarly monitored for intravascular haemolysis by measuring LDH levels, and may require dose adjustment within the recommended 14±2 day dosing schedule during the maintenance phase (up to every 12 days).
aHUS Laboratory Monitoring: aHUS patients receiving Soliris therapy should be monitored for thrombotic microangiopathy by measuring platelet counts, serum LDH and serum creatinine, and may require dose adjustment within the recommended 14±2 day dosing schedule during the maintenance phase (up to every 12 days).
Treatment Discontinuation for PNH: If PNH patients discontinue treatment with Soliris they should be closely monitored for signs and symptoms of serious intravascular haemolysis. Serious haemolysis is identified by serum LDH levels greater than the pre-treatment level, along with any of the following: greater than 25% absolute decrease in PNH clone size (in the absence of dilution due to transfusion) in one week or less; a haemoglobin level of <5 g/dL or a decrease of >4 g/dL in one week or less; angina; change in mental status; a 50% increase in serum creatinine level; or thrombosis. Monitor any patient who discontinues Soliris for at least 8 weeks to detect serious haemolysis and other reactions.
If serious haemolysis occurs after Soliris discontinuation, consider the following procedures/treatments: blood transfusion (packed RBCs), or exchange transfusion if the PNH RBCs are >50% of the total RBCs by flow cytometry; anticoagulation; corticosteroids; or reinstitution of Soliris. In PNH clinical studies, 16 patients discontinued the Soliris treatment regimen. Serious haemolysis was not observed.
Treatment Discontinuation for aHUS: Severe thrombotic microangiopathy complications were observed after Soliris discontinuation in the aHUS clinical studies. If aHUS patients discontinue treatment with Soliris they should be monitored closely for signs and symptoms of severe thrombotic microangiopathy complications.
Severe thrombotic microangiopathy complications post discontinuation can be identified by (i) any two, or repeated measurement of any one, of the following: a decrease in platelet count of 25% or more as compared to either baseline or to peak platelet count during Soliris treatment; an increase in serum creatinine of 25% or more as compared to baseline or to nadir during Soliris treatment; or, an increase in serum LDH of 25% or more as compared to baseline or to nadir during Soliris treatment; or (ii) any one of the following: a change in mental status or seizures; angina or dyspnoea; or thrombosis.
Monitor any patient who discontinues Soliris for at least 12 weeks to detect severe thrombotic microangiopathy complications.
If severe thrombotic microangiopathy complications occur after Soliris discontinuation, consider reinstitution of Soliris treatment, supportive care with PE/PI, or appropriate organ-specific supportive measures including renal support with dialysis, respiratory support with mechanical ventilation or anticoagulation. In aHUS clinical studies, 18 patients (5 in the prospective studies) discontinued Soliris treatment. Seven (7) severe thrombotic microangiopathy complications were observed following the missed dose in 5 patients and Soliris was re-initiated in 4 of these 5 patients.
Educational guidance: All physicians who intend to prescribe Soliris must ensure they are familiar with the physician's guide to prescribing. Physicians must discuss the benefits and risks of Soliris therapy with patients and provide them with a patient information brochure and a patient safety card.
Patients should be instructed that if they develop fever > 39°C, headache accompanied with fever and/or stiff neck or sensitivity to light, they should immediately seek medical care as these signs may be indicative of meningococcal infection.
Excipients: This medicinal product contains 5.00 mmol sodium per dose (1 vial). It should be taken into consideration by patients on a controlled sodium diet.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
No interaction studies have been performed.
4.6 Pregnancy And Lactation
Pregnancy:
For Soliris, no clinical data on exposed pregnancies are available.
Animal reproduction studies have not been conducted with eculizumab (see section 5.3).
Human IgG are known to cross human placental barrier, and thus eculizumab may potentially cause terminal complement inhibition in the foetal circulation. Therefore, Soliris should be given to a pregnant woman only if clearly needed. Woman of childbearing potential have to use effective contraception during treatment and up to 5 months after treatment.
Breast-feeding:
It is unknown whether eculizumab is excreted into human milk. Since many medicinal products and immunoglobulins are secreted into human milk, and because of the potential for serious adverse reactions in nursing infants, breast-feeding should be discontinued during treatment and up to 5 months after treatment.
4.7 Effects On Ability To Drive And Use Machines
No studies on the effects on the ability to drive and use machines have been performed.
4.8 Undesirable Effects
a. Summary of the safety profile
Eculizumab for the treatment of PNH was studied in three clinical studies that included 195 eculizumab-treated patients and most of these patients have been enrolled in the E05-001 extension study. There was one pivotal trial comparing the eculizumab-treatment arm to a placebo-treatment arm.
Eculizumab for the treatment of aHUS was studied in 37 patients enrolled in two prospective controlled clinical studies (C08-002A/B and C08-003A/B). Additional safety data were collected in 30 patients in a retrospective study (C09-001r).
The most frequent adverse reactions were:
- Headache, dizziness, nausea and pyrexia each occurring in 5% or more in PNH clinical trials. Most headaches did not persist after the initial administration phase of Soliris.
- Leukopenia occurring in 10% or more in aHUS clinical trials
b. Tabulated summary of adverse reactions
Table 1 gives the adverse reactions observed from spontaneous reporting and in clinical trials in PNH and aHUS. Adverse reactions reported at a very common (
Table 1: Adverse Reactions Reported in 232 patients included in PNH and aHUS clinical trials and in postmarketing reports
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*See paragraph. c. Description of selected adverse reactions
c. Description of selected adverse reactions
There was no evidence of an increased incidence of infection across PNH studies with eculizumab as compared to placebo, including serious infections, severe infections or multiple infections.
In all PNH clinical studies the most serious adverse reaction was meningococcal septicaemia in two vaccinated PNH patients (see section 4.4). There were no meningococcal infections or deaths in the aHUS clinical studies. There did not appear to be evidence for an increased risk of other serious infections with eculizumab treatment in the aHUS studies.
Low titres of antibodies were detected in 2% patients with PNH treated with Soliris. As with all proteins there is a potential for immunogenicity.
Cases of haemolysis have been reported in the setting of missed or delayed Soliris dose in PNH clinical trials (see also Section 4.4).
Cases of thrombotic microangiopathy have been reported in the setting of missed or delayed Soliris dose in aHUS clinical trials (see also Section 4.4).
d. Paediatric population
The safety profile in paediatric aHUS patients in the retrospective study C09-001r (N=15, patients ages 2 months to less than 12 years) treated with Soliris appeared similar to that observed in adult/adolescent aHUS patients. The most common (>10%) adverse events reported in paediatric patients were diarrhoea, vomiting, pyrexia, upper respiratory tract infection and headache.
Safety Data From Other Clinical Studies
Supportive safety data were obtained in 11 clinical studies that included 716 patients exposed to eculizumab in six disease populations other than PNH and aHUS. There was an un-vaccinated patient diagnosed with idiopathic membranous glomerulonephropathy who experienced meningococcal meningitis. With regard to other AEs and considering all double-blind, placebo-controlled studies in patients diagnosed with diseases other than PNH (N=526 patients with Soliris; N=221 patients with placebo), AEs reported with Soliris at a frequency of 2% or greater than the frequency reported with placebo were: upper respiratory tract infection, rash, and injury.
4.9 Overdose
No case of overdose has been reported.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Pharmacotherapeutic group: Immunomodulators, ATC code: L04AA25
Soliris is a recombinant humanised monoclonal IgG2/4k antibody that binds to the human C5 complement protein and inhibits the activation of terminal complement. The Soliris antibody contains human constant regions and murine complementarity-determining regions grafted onto the human framework light- and heavy-chain variable regions. Soliris is composed of two 448 amino acid heavy chains and two 214 amino acid light chains and has a molecular weight of approximately 148kDa.
Soliris is produced in a murine myeloma (NS0 cell line) expression system and purified by affinity and ion exchange chromatography. The bulk drug substance manufacturing process also includes specific viral inactivation and removal steps.
Mechanism of Action
Eculizumab, the active ingredient in Soliris, is a terminal complement inhibitor that specifically binds to the complement protein C5 with high affinity, thereby inhibiting its cleavage to C5a and C5b and preventing the generation of the terminal complement complex C5b-9. Eculizumab preserves the early components of complement activation that are essential for opsonization of microorganisms and clearance of immune complexes.
In PNH patients, uncontrolled terminal complement activation and the resulting complement mediated intravascular haemolysis are blocked with Soliris treatment.
In most PNH patients, eculizumab serum concentrations of approximately 35 microgram/ml are sufficient for essentially complete inhibition of terminal complement-mediated intravascular haemolysis.
In PNH, chronic administration of Soliris resulted in a rapid and sustained reduction in complement-mediated haemolytic activity.
In aHUS patients, uncontrolled terminal complement activation and the resulting complement mediated thrombotic microangiopathy are blocked with Soliris treatment.
All patients treated with Soliris when administered as recommended demonstrated rapid and sustained reduction in terminal complement activity. In all aHUS patients, eculizumab serum concentrations of approximately 50-100 microgram/ml are sufficient for essentially complete inhibition of terminal complement activity.
In aHUS, chronic administration of Soliris resulted in a rapid and sustained reduction in complement mediated thrombotic microangiopathy.
Clinical efficacy and safety
Paroxysmal Nocturnal Haemoglobinuria
The safety and efficacy of Soliris in PNH patients with haemolysis were assessed in a randomized, double-blind, placebo-controlled 26 week study (C04-001); PNH patients were also treated with Soliris in a single arm 52 week study (C04-002); and in a long term extension study (E05-001). Patients received meningococcal vaccination prior to receipt of Soliris. In all studies, the dose of eculizumab was 600 mg every 7 ± 2 days for 4 weeks, followed by 900 mg 7 ± 2 days later, then 900 mg every 14 ± 2 days for the study duration. Eculizumab was administered as an intravenous infusion over 25 – 45 minutes.
In study C04-001 (TRIUMPH) PNH patients with at least 4 transfusions in the prior 12 months, flow cytometric confirmation of at least 10% PNH cells and platelet counts of at least 100,000/microliter were randomized to either Soliris (n = 43) or placebo (n = 44). Prior to randomization, all patients underwent an initial observation period to confirm the need for RBC transfusion and to identify the haemoglobin concentration (the "set-point") which would define each patient's haemoglobin stabilization and transfusion outcomes. The haemoglobin set-point was less than or equal to 9 g/dL in patients with symptoms and was less than or equal to 7 g/dL in patients without symptoms. Primary efficacy endpoints were haemoglobin stabilization (patients who maintained a haemoglobin concentration above the haemoglobin set-point and avoid any RBC transfusion for the entire 26 week period) and blood transfusion requirement. Fatigue and health-related quality of life were relevant secondary endpoints. Haemolysis was monitored mainly by the measurement of serum LDH levels, and the proportion of PNH RBCs was monitored by flow cytometry. Patients receiving anticoagulants and systemic corticosteroids at baseline continued these medications. Major baseline characteristics were balanced (see table 2).
In the non-controlled study C04-002 (SHEPHERD), PNH patients with at least one transfusion in the prior 24 months and at least 30,000 platelets/microliter received Soliris over a 52-week period. Concomitant medications included anti-thrombotic agents in 63% of the patients and systemic corticosteroids in 40% of the patients. Baseline characteristics are shown in Table 2.
Table 2: Patient Demographics and Characteristics in C04-001 and C04-002
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In TRIUMPH, study patients treated with Soliris had significantly reduced (p< 0.001) haemolysis resulting in improvements in anaemia as indicated by increased haemoglobin stabilization and reduced need for RBC transfusions compared to placebo treated patients (see table 3). These effects were seen among patients within each of the three pre-study RBC transfusion strata (4 - 14 units; 15 - 25 units; > 25 units). After 3 weeks of Soliris treatment, patients reported less fatigue and improved health-related quality of life. Because of the study sample size and duration, the effects of Soliris on thrombotic events could not be determined. In SHEPHERD study, 96 of the 97 enrolled patients completed the study (one patient died following a thrombotic event). A reduction in intravascular haemolysis as measured by serum LDH levels was sustained for the treatment period and resulted in increased transfusion avoidance, a reduced need for RBC transfusion and less fatigue. See Table 3.
Table 3: Efficacy Outcomes in C04-001 and C04-002
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